Project 2. The generation of an effective AIDS vaccine is greatly complicated by our incomplete knowledge of the correlates of immune protection during HIV infection. It has been difficult to compare the potential clinical efficacy of the numerous vectors currently considered as platforms for candidate AIDS vaccines. Notwithstanding these conceptual limitations, a number of clinical and pre-clinical immunogenicity studies using state-of-the-art assays indicate that replication-defective adenovirus (Ad) vectors based on the human serotype 5 (AdHuS) can robustly induce strong and persistent immune responses to HIV/SIV antigens. Unfortunately, pre-existing exposure and/or immunity to human Ads, and particularly to AdHuS, may hamper the efficacy of AdHuS-based candidate AIDS vaccines. The overarching hypothesis of this IPCAVD proposal is that chimpanzee (chimp) Adenovirus (AdC)-based vectors represent promising candidate AIDS vaccines as they show a profile of immunogenicity that is as good, if not better, than that observed for AdHuS while presenting only minor problems in terms of pre-existing immunity. The use of AdC6 and AdC7 as vaccine vectors was pioneered in a series of pivotal studies conducted in the laboratory of Dr. Ertl. In Project #2 we propose to study in detail the cellular immune responses generated by different immunization strategies that include various combinations of AdC-based candidate HIV/SIV vaccines used in prime-boost regimens. We will perform contemporary immunological studies to assess the level of cellular immune responses induced by the tested vectors. The phenotypes, properties, and functions of the HIV/SIV-specific CD4+ and CD8+ T cell-mediated responses induced by different AdC-based vaccination regimens will be defined, and compared to the T cell responses that arise following experimental SIV infections of both vaccinated and unvaccinated animals. In addition, we will determine the level of protection from SIV challenge in rhesus macaques that are vaccinated with different protocols. Ultimately, the proposed studies are aimed at defining the efficacy of AdC-based candidate AIDS vaccines in inducing host responses that can contain virus replication, prolong disease-free survival, and decrease secondary transmission. Definition of the characteristics of such effective immune responses will also advance our understanding of the correlates of immune protection to be pursued in future efforts of AIDS vaccine development.